The compound (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one (also herein referred to as “Compound I”) represented by the formula I

is a potent small-molecule multi-target kinase inhibitor showing activity against wild-type and mutant ALK (anaplastic lymphoma kinase), wild-type and mutant ROS1 (ROS1 proto-oncogene receptor tyrosine kinase), the TRK family of kinases (tropomyosin-related receptor tyrosine kinases), JAK2 of the Janus family of kinases, SRC (Src family of protein tyrosine kinases (SFKs)) and FAK (focal adhesion kinase). Compound I has properties, including anti-tumor properties, that are pharmacologically mediated through inhibition of tyrosine kinase receptors. Compound I is disclosed in International Patent Application No. PCT/US2015/012597, which is incorporated herein by reference in its entirety.
Protein kinases are key regulators for cell growth, proliferation and survival. A variety of diseases, such as cancer, pain, neurological diseases, autoimmune diseases, and inflammation, have been shown to be mediated by receptor tyrosine kinases, such as ALK, ROS1, TRK, JAK2, SRC and FAK. For example, genetic and epigenetic alterations can accumulate in cancer cells leading to abnormal activation of signal transduction pathways which drive malignant processes. Manning, G. et al., Science 2002, 298, 1912-1934. Pharmacological inhibition of these signaling pathways presents promising intervention opportunities for targeted cancer therapies. Sawyers, C., Nature 2004, 432, 294-297.
While Compound I has found application in treating disease associated with receptor tyrosine kinases, such as ALK, ROS1, TRK, JAK2, SRC and FAK, it is advantageous to have polymorphic forms having improved properties, such as improved crystallinity, dissolution properties, and/or decreased hygroscopicity, while maintaining chemical and enantiomeric stability properties.